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Circulation on the Run

Apr 6, 2020

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

Dr Greg Hundley: I'm Greg Hundley, associate editor from the VCU Pauley Heart Center in Richmond, Virginia.

Dr Carolyn Lam: Greg today's speaker paper is all about soy products and whether or not there is a benefit with them with regards to risk of coronary heart disease. Now, this has been extremely controversial and today's speech or paper is really important in its findings. Ha ha, I bet you want to get to it right now but I'm going to say, hold on let's get to some other really interesting papers in this series first. Can I start off? You got your coffee?

Dr Greg Hundley: Yes. Let's get going Carolyn.

Dr Carolyn Lam: So the first paper I want to highlight really talks about myocardial energetics in obesity, and you're going to love this one Greg it's got some really cool MRI techniques. We know that obesity is strongly associated with exercise intolerance and the development of heart failure particularly HFpEF. Well Dr Rayner from University of Oxford and colleagues looked at this carefully in 80 volunteers, which included 35 controls with an average BMI of 24 and 45 obese individuals with an average BMI of 35, who did not have coexisting cardiovascular disease. Now, these participants underwent body composition analysis and MRI of the abdominal liver and myocardial fat content, left ventricular function and 31 Phosphorus Magnetic Resonance Spectroscopy to assess Phosphocreatine ATP and Creatine Kinase Kinetics at rest and during Dobutamine Stress.

Dr Greg Hundley: Oh, wow Carolyn, this is right up my alley. You've got MRI imaging for body composition coupled with MR spectroscopy for metabolism, so what did they find?

Dr Carolyn Lam: Thanks for putting that simply for us Greg. They found that in the obese resting heart, the myocardial creatine kinase reaction rate is increase, maintaining ATP delivery despite reduced energy stores during increased workload. While the non obese heart increases ATP delivery through creatine kinase the obese heart does not, and this is associated with reduced systolic augmentation and exercise tolerance. Weight Loss reversed these energetic changes, so these findings really highlight myocardial energy delivery via creatine kinase as a potential therapeutic strategy to improve symptoms in obesity related heart disease, as well as a fascinating modifiable pathway involved in the progression to heart failure. Now with this paper the central illustration is so critical, everybody has to pick up that issue and have a look. Furthermore, you must read the elegant editorial by Barry Borlaug and Craig Malloy.

Dr Greg Hundley: Oh, you bet Carolyn. Craig always puts these MR spectroscopy papers in such fantastic perspective, really looking forward to that read and such an elegant study. Now, we haven't had Carolyn's quiz in weeks and we're going to get into one. This paper comes from Professor Nina Wettschureck, from the Max-Planck-Institute for Heart and Lung research, and it pertains to the infamous G-protein coupled receptors. Now, Carolyn here's your quiz and guess what, it's just multiple choice. All you have to do is fill in the blank.

Dr Carolyn Lam: On G-protein coupled receptors?

Dr Greg Hundley: Yeah, I know it's... we know a lot about these, but we're going to learn. So, G-protein coupled receptors are the largest family of transmembrane receptors in eukaryotes. They transduce signals of numerous physio-chemical stimuli including... and Carolyn you have to complete this sentence. So it's neurotransmitters, hormones, local mediators, metabolic or olfactory cues and got to complete the sentence. Is it air resistance? Time? Or light?

Dr Carolyn Lam: Space.

Dr Greg Hundley: That's not a choice.

Dr Carolyn Lam: All right, all right let me guess light.

Dr Greg Hundley: That's awesome. Fantastic, great job Carolyn. So in the vascular system the contract alternative vessels is crucially regulated by these GPCRs, including basic constrictors such as Angiotensin two and Endothelin one. In this study the investigators studied the role of GPRC5B, and the regulation of contractility and differentiation in human and murine smooth muscle cells in vitro, as well as in tamoxifen inducible smooth muscle cells Pacific knockout mice under conditions of arterial hypertension and atherosclerosis, and these experiments were done in vivo.

Dr Carolyn Lam: Okay, so what were the results?

Dr Greg Hundley: They found that GPRC5B regulates vascular smooth muscle tone and differentiation by negatively regulating prostate cycling receptor signaling. Thus, Carolyn inhibition of the interaction between GPRC5B and the prostacyclin receptor might be beneficial in human arterial hypertension and vascular remodeling. What a great new insight into basic science. Well, let me get on I have a clinical paper, and this is on the infamous topic from the COMPASS-PCI trial, Rivaroxaban plus Aspirin versus Aspirin alone in patients with Prior Percutaneous Coronary Intervention from Dr Kevin Bainey at the Canadian VIGOUR Center in University of Alberta.

So Carolyn, the cardiovascular outcomes for people using anticoagulation strategies or COMPASS trial demonstrated dual pathway intervention with Rivaroxaban 2.5 milligrams twice daily plus aspirin, and 100 milligrams once daily versus aspirin 100 milligrams once daily, reduced the primary major adverse cardiovascular event outcome of cardiovascular death, MI or stroke as well as mortality in patients with chronic coronary syndromes or peripheral arterial disease. Now, whether this remains true in patients with a history of PCI is unknown.

Dr Carolyn Lam: Oh, Greg I'm so disappointed. Why didn't you give me a quiz here? I know about the COMPASS trial. Okay, so what did the author's find?

Dr Greg Hundley: So Carolyn of the 27,000 plus patients in COMPASS 16,500 plus patients had chronic coronary syndrome, were randomized to DPI or aspirin and of these 9,862 had prior PCI. So here are the results, DPI compared with aspirin produce consistent reductions in MACE mortality, but with increased major bleeding with or without prior PCI. So among those with prior PCI one year and beyond, the effects on MACE and mortality were consistent irrespective of time since the last PCI.

Dr Carolyn Lam: Mm-hmm (affirmative) Interesting implications on dual platelet inhibition. Well, let me tell you a little bit about what's in the mailbag in the rest of this issue. There's a research letter by Dr Joseph Wu on molecular signatures of beneficial class effects of statins on human induced pluripotent stem cell derived cardiomyocytes. We have global rounds by Dr Annika Rosengren and Dr Lars Wallentin on the cardiovascular medicine in Sweden. We have a White Paper by Dr Abhinav Saxena and colleagues on the value of hemodynamic monitoring in patients with cardiogenic shock undergoing mechanical circulatory support. And we also have paired perspective pieces, one by Dr Salim Virani and colleagues on secondary prevention of atherosclerotic cardiovascular disease comparing recent United States and European guidelines on dyslipidemia, and another by Dr Neil Stone and colleagues on comparing primary prevention recommendations with the focus look at the US versus European guidelines on dyslipidemia.

Dr Greg Hundley: Very good, Carolyn. Well, I've got a research letter Professor Do-Young Kwon from the Korea University of Ansan Hospital, Korea University College of Medicine and discusses the association of Parkinson's disease with the risk of cardiovascular disease and all-cause mortality, and a nationwide population-based cohort study. In addition, different series of letters Dr Seung-Jung Park from Asan Medical Center at the University of Ulsan College of Medicine, and Professor Lang Li of The First Affiliated Hospital of Guangxi Medical University exchanged letters regarding the article, Clinically Significant Bleeding With Ticagrelor versus Clopidogrel in Korean patients with Acute Coronary Syndromes Intended for Invasive Management, that previously published randomized clinical trial. Then finally one of those great ECG investigations from Dr Miguel Arias, and they have an ECG quiz entitled The Hidden Reveals the Hidden, but really, it's referring to a Brugada ECG pattern and a patient with Wolff-Parkinson-White. I can't wait to get onto that feature article discussing the potential benefits or harms of soy in men and women as it relates to cardiovascular disease.

Dr Carolyn Lam: Yeah, you and I Greg let's go. Oh, boy today's feature paper really literally cuts close to the heart for me talking about soy products, and whether or not there's a relationship with cardiovascular health. This remains controversial but thankfully we've got really great data just published in this week's issue, so proud to have the first author with us Dr Qi Sun from Brigham and Women's Hospital, as well as our associate editor who's also an editorialist for this paper and that's Dr Mercedes Carnethon from Northwestern University Feinberg School of Medicine. So welcome both I cannot wait to just jump right into it. Please, Qi, tell us what you found about soy products.

Dr Qi Sun: First off this is a prospective cohort study that included three cohort studies, the Nurses’ Health Study and the Nurses’ Health Study II and Health Professionals Follow-Up Study. So those three big prospective cohort follow up studies. Now over the years we have collected much data of diet which has been repeated, reviewed, and assessed over the years, and we have accumulated many cases of cardinal heart disease the numbers are a solid. Now what we found is that the intake isoflavones which are the big family are flavonoids, the higher intake of isoflavones were associated with a lower risk of developing coronary heart disease in those three cohorts of men and women. And in addition because tofu and soy milk are the primary contributor in our guide of isoflavones, we also examine the tofu and soy milk in relation to the risk of cardinal heart disease What we found is that tofu intake is significantly associated with lower risk of developing heart disease, and soy milk is also associated with lower risk of developing heart disease. It's just the association for soy milk, soy milk is not significant. And I think very interestingly we also found that the menopausal status and the postmenopausal hormone use somewhat also modulated association primarily for coffee intake with heart disease risk, in that we found younger women who were before their menopause and also postmenopausal women who did not use hormone will benefit more from tofu intake.

In contrast, for postmenopausal women who are using hormone the association was not significant. I think those are the primary findings of our prospective cohort study.

Dr Carolyn Lam: Oh my goodness, hallelujah. That's really marvelous and beautifully summarized, Mercedes please explain why was this such a controversial area before? And what does this paper add? Love your editorial by the way.

Mercedes Carnethon: We hear a lot about nutritional epidemiology studies, and we have a lot of debates about what we should believe, whether we should change our behavior based on these observational studies and quite often we have discussions about what's new. And I lean on that final point about why I like this particular paper so much, and that's because I found the topic of isoflavones, tofu intake and soy to be extremely relevant to a large proportion of the world's population, whose primary protein intake may be something made from a soybean, heavy and isoflavones. Within the United States it's also relevant even though a smaller proportion of our population relies primarily on vegetarian diet, there is a very large and interested group wondering whether soy intake is safe. There have been discussions about whether there's harm associated with it, and the possibility that it could have beneficial influence on our leading causes of death of coronary heart disease.

So I was most thrilled about the innovation of this particular topic, and its methodological rigor. When we think about what we lean on, we lean on large studies, we lean on multiple events and the size of the study allowed the investigators to explore numerous subtleties. Subtleties such as that reported related to the moderation by menopausal status, and that was the point I was most curious about and why I'm really excited to have an opportunity to talk to you today Chi. Can you tell me a little more about the menopausal status finding?

Dr Qi Sun: So first off as I mentioned tofu intake was more strongly associated with lower risk of developing heart disease among younger pre-menopausal women, or postmenopausal women who did not use ham. Before that I want to also mention for isoflavones intake where I also found a similar pattern in that isoflavones are more. Appear to be more strongly associated with lower risk also in those two groups of women, although the past by interaction was non-significant. Now in terms of why I think there are a couple reasons why is that, among postmenopausal female or in our use hormone, the isoflavone can function as estrogen and provide at least partially the estrogenic effects that were calculated in postmenopausal women who do not use hormone, and for premenopausal women we think that's probably because before menopausal, the activity of estrogen receptor may be higher than the estrogen receptor after menopausal. So, in reality, the other variables of isoflavones may provide estrogen effects after menopausal. So those are the hypotheses although I have to mention that those hypotheses, we need more evidence to really shed light on the mechanisms underlying those interactions between menopausal status, postmenopausal hormonal use, where's the intake of isoflavones and tofu.

Dr Carolyn Lam: So Chi I love that explanation and giving it some biological possibility, although as you said it's a postulation. But may I ask so what's the implication for men? I lived with a man who thinks if he takes soy he's going to grow boobs. So what... did you see any sex differences and do studies like this and able looking for the downsides of eating soy?

Dr Qi Sun: As a scientist I'm open to any kind of new findings as long as the findings are from well conducted, rigorously designed study. But having said that I couldn't exclude the possibility that maybe soy intake is associated with certain adverse health outcomes, but so far based on my experience I didn't see any such evidence. But having said this I always say I wouldn't risk any possibility, but coming... circling back to the coronary heart disease we really didn't see much difference between men and women. It's true for the younger women we saw a stronger association but for men I also see a lower risk of heart disease. So there's a kind of interesting image on soy intake or isoflavones intake in the United States that people believe they are estrogen so a man shouldn't take it, but if you look at the group of vegetarians, the vegans. There are a lot of guys they practice vegetarian, they practice vegan diets and we also publish on plant-based diet in relation to coronary heart disease and lot of men eat very healthy. And we found those people who practice those kinds of healthy diets, soy is often mouthful of primary sources of proteins and if you look at their risk of developing heart disease, type two diabetes is quite low. Something lower than other normal women who practice otherwise omnivore diet.

Dr Carolyn Lam: It's true Qi soy intake could also be a marker of a healthier lifestyle in general, by extension of what you just said. But Mercedes I love that you discuss quite a number of these issues in your editorial and at the end of the day you asked the most important question, what does this mean for us? Should we all be increasing our intake of soy products? Could you give us your synthesis of that?

Mercedes Carnethon: Yes, a point that I've definitely tried to make here, and this is really in response to what I expect to be the media fear surrounding new dietary findings. One of the first questions that I know that she and his colleagues will be asked is, should I change my diet? Can I extend my life? And that's because the media is really looking for a lot of sensational headlines in this topic, and I think we have to focus on what we learn from these observational studies. They're a very important step in the scientific process that helps us provide a justification for later clinical trials, that helps us think about the multiple components that work together to promote overall excellent health. And the point you were making right before this about the individuals who eat plant based diets that are heavily based in soy. In the paper it also describes that those individuals exercise more, they may have lower intakes of saturated fat, and so I think ultimately what I take from this at least for myself and for people who would ask is that an overall healthy diet seems to stand up very well in these well done observational studies. And that soy in particular may be a part of an overall healthy diet given what we're seeing here in this very well done study.

Dr Carolyn Lam: Oh, that's beautifully put Mercedes and Chi perhaps I can give you the last word. What would you say is the take home message and what are next steps?

Dr Qi Sun: I think the core message is this as Mercedes very well discussed, I think soy and especially tofu can be really good components of the overall healthy plant based diet, and by practicing that I think we can significantly reduce the risk of developing coronary heart disease for both men and the women. I think moving forward we would like to see evidence from clinical trials that target cardiometabolic risk factors as outcome, and to see whether increased consumption of tofu and isoflavones can really reduce those risk markers so that they have ample evidence to support the mechanisms. As you mentioned Carolyn that this is an initial study, and it could be soy, intake could be just macro how is it, through clinical trials, we can really control those confounding factors and really provide good evidence to support our findings.

Dr Carolyn Lam: Well, in the meantime I just have to say you made my day this is coming from a soy eating vegetarian, so thank you so, so much. Thank you, listeners for joining us today.

Dr Greg Hundley: This program is copyright the American Heart Association 2020.